Regulation of Appetite and Obesity by PACAP

PACAP 调节食欲和肥胖

• 批准号: 8480601
• 负责人: Patricia Maria Germano
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480601
• 关键词: Accounting; Address; Adult; Affinity; Afghanistan; Animal Feed; Animal Model; Animals; Appetite Regulation; Biological; Blood; Body Composition; Body Weight; Body fat; Caring; Cell model; Cells; Cellular biology; Cerebrovascular Disorders; Cessation of life; Chronic; Clinical; Clinical Research; Coronary Arteriosclerosis; Data; Department of Defense; Desire for food; Development; Diabetes Mellitus; Diet; Diet Monitoring; Dietary Proteins; Disease; Eating; Eating Behavior; Enterochromaffin Cells; Equipment; Fatty acid glycerol esters; Feeding behaviors; Financial compensation; Functional disorder; Future; Gastric mucosa; Gastrointestinal Hormones; Gastrointestinal tract structure; Gene Expression; Goals; Hormones; Human; Hyperphagia; Hypertension; Hypothalamic structure; In Vitro; Ingestion; Investigation; Leptin; Mass Behavior; Measurement; Measures; Mediating; Medical; Medical center; Military Personnel; Modeling; Molecular Biology; Molecular Profiling; Morbidity - disease rate; Mucous Membrane; Mus; Neuroendocrine Cell; Neuropeptides; Neurosecretory Systems; Obesity; PACAPR-1 protein; Pathway interactions; Patients; Pensions; Peptide Signal Sequences; Peptides; Peripheral; Physiological; Play; Prevalence; Proteins; Regulation; Regulatory Pathway; Rehabilitation therapy; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Satiation; Secretory Cell; Serum; Signal Transduction; Signal Transduction Pathway; Stomach; Stroke; System; Techniques; Veterans; War; World Health Organization; abdominal fat; adipokines; analog; base; cytokine; design; feeding; gastrointestinal; genetic profiling; ghrelin; glucagon-like peptide 1; in vivo; interdisciplinary collaboration; mortality; mouse model; neurophysiology; novel strategies; novel therapeutics; obesity treatment; pandemic disease; pituitary adenylate cyclase activating polypeptide; preclinical study; programs; public health relevance; receptor; response; therapeutic target; translational study

DESCRIPTION (provided by applicant): The World Health Organization (WHO) has classified obesity as a worldwide pandemic, resulting in about 300,000 deaths per year in U.S. adults and $80 billion in expenses (1-11). Obesity is a major cause of morbidity and mortality within our VA medical system accounting for the majority of cases of diabetes mellitus, hypertension, coronary artery disease and cerebrovascular accidents. The current understanding of the regulation of eating behavior and obesity suggests that both central and peripheral receptors and pathways control appetite. High protein diets have been described to reduce appetite, but the mechanisms are unknown. Our research program has been focused on the role of the recently discovered neuropeptide, Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and its high affinity receptor, PAC1, in the regulation of appetite and in the development of obesity. PACAP is released in the hypothalamus, where it acts with a dual mechanism: it activates the anorexigenic alpha- melanocortin pathway and it stimulates the release of the orexigenic PYY neuropeptide. The peripheral pathway by which PACAP regulates appetite has not been previously explored. Previously, we have shown that PACAP is released from the gastric mucosa cells in response to meal stimulation and that neuroendocrine of the stomach express PAC1 to regulate gastrointestinal physiological function. For this proposal, we have developed a PAC1 deficient mouse model (PAC1-/-) and have demonstrated that these mice develop hyperphagia and obesity and thus serve as a useful model to investigate the regulatory pathways mediating obesity. Based on these preliminary data, our central hypothesis is that PACAP, released in the stomach following protein ingestion, stimulates PAC1 expressed on gastric neuroendocrine cells to inhibit ghrelin release, thereby suppressing appetite. Accordingly, in Aim 1 of the proposal we will study the relationship between dietary protein content, PACAP release and effects on the downstream pathways connecting PAC1 and ghrelin release. To accomplish this we propose to utilize our PAC1 deficient mice and assess the response to protein dietary content, body mass and feeding behavior. The feeding behavior will be analyzed using our recently acquired BIODAQ equipment, EchoMRI to measure mouse fat and lean mass. The serum levels of PACAP, ghrelin and of a panel of obesity associated hormones and cytokines will be measured using Luminex. The second specific aim of the proposal will investigate the in vitro cellular responses to luminal protein using our recently developed cellular isolation techniques. Microarray and RT-PCR studies will be used to analyze genetic profiles of isolated ECL and X/A. A clear understanding of the key pathophysiological mechanisms underlying these PACAP- induced regulatory pathways involved in appetite/satiety regulation, will allow the design of future clinical studies with a focus on therapy. The proposed studies will elucidate the peripheral mechanisms, by which PACAP influences protein-induced satiety which will provide an important therapeutic target for the development of novel therapeutic compounds which would be used to treat obesity in our Veterans and active duty military personnel. PUBLIC HEALTH RELEVANCE: Within the VA Medical Care Centers and Department of Defense, the prevalence of obesity has been increasing over the past decade and is a major cause of morbidity, mortality and making rehabilitation more difficult for our Veterans. The increasing prevalence of obesity not only leads to the development of chronic medical conditions, such as diabetes mellitus, hypertension, coronary artery disease and cerebrovascular disease, but also it is likely to be a reason for compensation and pension benefits for many of our returning Gulf and Afghanistan War Veterans. Accordingly, this proposal is directed at understanding key gastrointestinal mechanisms for regulating feeding behavior using our recently developed animal model of obesity with the overarching purpose of applying these finding to develop novel approaches for clinically regulating appetite, body composition and weight in veteran patients with obesity- related disorders.

描述（由申请人提供）： 世界卫生组织（WHO）将肥胖症分类为全球大流行，每年在美国成年人每年约30万人死亡，费用为800亿美元（1-11）。 肥胖是我们VA医疗系统中发病率和死亡率的主要原因，该系统涉及大多数糖尿病，高血压，冠状动脉疾病和脑血管事故的病例。当前对饮食行为和肥胖症调节的理解表明，中央受体和外围受体以及途径控制食欲。已经描述了高蛋白质饮食可减少食欲，但机制尚不清楚。我们的研究计划集中在最近发现的神经肽，垂体腺苷酸环化酶激活多肽（PACAP）及其高亲和力受体PAC1中的作用，对食欲调节和肥胖的发展。 PACAP在下丘脑中释放，它具有双重机制：它激活了厌食症α-黑色素皮质素途径，并刺激了Orecigenic Pyy Pyy神经肽的释放。先前尚未探索PACAP调节食欲的外围途径。 以前，我们已经表明，PACAP是从胃粘膜细胞中释放出来的，以响应餐刺激，并且胃表达PAC1的神经内分泌可调节胃肠道生理功能。对于此建议，我们开发了PAC1缺陷的小鼠模型（PAC1 - / - ），并证明这些小鼠会发展出脾气和肥胖，因此是研究介导肥胖症的调节途径的有用模型。基于这些初步数据，我们的中心假设是，摄入蛋白质后在胃中释放的PACAP刺激了在胃神经内分泌细胞上表达的PAC1，以抑制生长素素的释放，从而抑制食欲。因此，在提案的目标1中，我们将研究饮食蛋白含量，PACAP释放和对连接PAC1和Ghrelin释放的下游途径的影响之间的关系。为此，我们建议利用我们的PAC1缺乏小鼠，并评估对蛋白质饮食含量，体重和喂养行为的反应。将使用我们最近获得的BioDAQ设备Echomri分析喂养行为，以测量小鼠脂肪和瘦质量。 PACAP，生长素蛋白和肥胖相关的激素和细胞因子的血清水平将使用Luminex进行测量。该提案的第二个具体目的将使用我们最近开发的细胞分离技术研究体外细胞对腔蛋白的反应。 微阵列和RT-PCR研究将用于分析分离的ECL和X/A的遗传谱。对这些PACAP诱导的调节途径所涉及的食欲/饱腹感的调节途径的关键病理生理机制的清晰了解将允许设计未来的临床研究，重点是治疗。拟议的研究将阐明外围机制，PACAP会影响蛋白质诱导的饱腹感，这将为开发新型治疗化合物的发展提供重要的治疗靶标，这些治疗化合物将用于治疗我们的退伍军人和现役军人的肥胖症。 公共卫生相关性： 在VA医疗保健中心和国防部，肥胖症的流行在过去十年中一直在增加，这是发病率，死亡率和使我们的退伍军人更加困难的主要原因。肥胖症的患病率不仅会导致慢性医疗状况的发展，例如糖尿病，高血压，冠状动脉疾病和脑血管疾病，而且还可能是我们许多返回海湾和阿富汗战争退伍军人的赔偿和养老金的理由。因此，该提案旨在理解关键的胃肠道机制，以使用我们最近开发的肥胖动物模型来调节喂养行为，其总体目的是将这些发现应用于临床调节食欲，身体组成和体重的新方法，以促进患有肥胖相关疾病的退伍军人。